This competitive revision application is submitted in response to NOT-OD-09-058 (Enabling RPGs to Leverage NCRR Center and Center-like Programs). Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) and is responsible for long-term morbidity in over 400,000 people in the United States. Although the precise etiology of MS is unknown, it is thought to be a T-cell-mediated process due to characteristic histologic features and the presence of neuroantigen-specific immune responses in the blood and cerebrospinal fluid. Thus, several immunomodulatory therapies are being investigated to combat this disease. Glatiramer acetate (GA, Copaxone) is an immune modulatory agent that is FDA-approved for the treatment of RRMS. However, the mechanism of its action still remains poorly understood. We have provided the first direct evidence that Copaxone induces not only CD4+, but also CD8+ T cell responses. Copaxone- specific CD8+ T cell responses are deficient in untreated MS patients and are restored during Copaxone therapy. We have thus uncovered a novel mechanism through which this FDA-approved drug may mediate its immunologic effects. The immediate immune effects of GA therapy have not been studied thus far. We hypothesize that the immunologic effects within the first 72 hours of therapy initiation would determine the long- term immune restoration and clinical responsiveness in MS patients. In this supplemental project, we will delineate the immediate effects of GA therapy on the function of APC and T cell subsets. These effects will then be evaluated for their predictive value in determining long-term immunologic and clinical benefit. Similar to studies in the currently funded parent grant, we believe these supplemental studies will provide important insights into MS immunology and will help generate better immunotherapeutic strategies. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system (CNS). Glatiramer acetate (GA, Copaxone) is an immune modulatory agent that is FDA-approved for the treatment of RRMS. However, the mechanism of its action still remains poorly understood. In this project, we will dissect the early immunologic events that follow the initiation of GA therapy. In particular, we will ask whether these early events are predictive of long-term immunologic and clinical benefit in MS patients. We believe these studies will provide important insights into an overlooked area of MS immunology and will help generate better immunotherapeutic strategies in the future.